1. Field of the Invention
The invention generally relates to cinnamic acid-based oligomers and therapeutic uses thereof. In particular, the invention provides cinnamic acid-based oligomers, and subsets thereof, for use as anti-coagulants, anti-inflammation agents, inhibitors of elastase and anti-oxidants.
2. Background of the Invention
1) Coagulation: Coagulation is a defense mechanism. It prevents excessive loss of blood following an injury as well as prevents infiltration of microbes. Yet, aberrant clotting is detrimental. Numerous disease states, including deep vein thrombosis and pulmonary embolism, arise due to inappropriate clotting. Inhibitors of thrombin and factor Xa have been primarily used to control inadvertent and inappropriate clotting. These include heparins (unfractionated heparin, low molecular weight heparin and fondaparinux) and coumarin derivatives (warfarin). Both of these agents suffer from major problems, e.g., enhanced bleeding risk, unpredictable response, etc. Newer agents that possess thrombin and factor Xa inhibition properties are actively being pursued.
Inhibitors of thrombin and factor Xa can be of two types—direct inhibitors and indirect inhibitors. Heparin are indirect inhibitors of thrombin and factor Xa, while hirudin, argatroban and rivaroxaban, two newer anticoagulants, are direct inhibitors. Direct inhibition of coagulation enzymes has been thought to be a better alternative, which promises to offer the important advantage of inhibition of both circulating and clot-bound thrombin. A prototypic member in this class of inhibitors is hirudin, which targets the active-site and exosite I of thrombin, and several derivatives of this peptide are now clinically available. Intensive efforts are also being made to develop the first orally bio-available direct thrombin inhibitor. These are small molecule pro-drugs that target the active site of these enzymes. However, challenges with these molecules include establishing enzyme binding affinity that is not associated with excessive bleeding, achieving inhibition of both clot-bound and unbound proteinases, and avoiding liver toxicity. Thus, there is an ongoing need for the development of alternative anti-coagulation agents.
2) Inflammation: Neutrophils play a critical role in host defense against invading pathogens. Pro-inflammatory mediators and chemotactic attractants activate neutrophils to engulf pathogens by phagocytosis. Neutrophil elastase is a potent serine protease that is released upon neutrophil activation in response to inflammatory signals that can destroy pathogens.
Neutrophil elastase cleaves and inactivates α1-proteinase inhibitor, tissue inhibitor of metalloproteinase, and complement fragment C3. It also appears that neutrophil elastase mimics the action of endogenous metalloproteinases directly activating degranulation and effectively bypassing the normal signal transduction pathways necessary for degranulation. Neutrophils constitutively express all membrane associated components of the nicotinamide-adenine-dinucleotide phosphate (NADPH) oxidase complex required to produce super oxide anion during a respiratory burst. Activation of neutrophils via chemotaxis receptors results in super oxide anion production. In the presence of low pH, super oxide anion is converted by super oxide dismutase into hydrogen peroxide and hydroxyl radicals which have intense anti-microbial properties. This pathway may contribute to the killing of protozoan, fungi and helminths.
Although beneficial for host defense against pathogens, aberrant activation of neutrophils and neutrophil elastase can also cause problems for its host and result in severe tissue damage. Neutrophil elastase is one of the most destructive enzymes in the body, with the capability of degrading extracellular matrix proteins (including collagens, proteoglycans, fibronectins, platelet receptors, complement receptors, thrombomodulin, lung surfactants and cadherins) and key plasma proteins (including coagulation and complement factors, immunoglobulins, several proteases and protease inhibitors). Under physiological conditions, endogenous protease inhibitors, such as α1-antitrypsin, tightly regulate the activity of neutrophil elastase. However, at inflammatory sites, neutrophil elastase is able to evade regulation, and once unregulated it can induce the release of pro-inflammatory cytokines, such as interleukin-6 and interleukin-8, leading to acute lung injury. Neutrophil elastase induction of IL-8 expression in bronchial epithelial cells, injures bronchial endothelial cells in part through the release of platelet activating factor (PAF), increases endothelial cell permeability, induces endothelial cell apoptosis, and degranulates eosinophils.
Acute lung tissue damage from aberrant neutrophil activation can lead to emphysema, chronic obstructive pulmonary disease, cystic fibrosis, and adult respiratory distress syndrome. Examples of non-respiratory diseases involving the inflammatory activity of neutrophil elastase are chronic inflammatory bowel disease, rheumatoid arthritis, and septic shock. There is a critical need to provide treatments for aberrant inflammation, elastase activity and oxidation.